Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the discovery of the hepatitis C virus (HCV) as the major cause of non-A, non-B hepatitis in 1989, the search for specific targeted antiviral therapy for HCV (STAT-C) has been underway. Recently, major advances in the understanding of HCV biology and the development of an in vitro system of HCV replication have contributed to the selection of multiple candidate drugs for the treatment of hepatitis C. In 2006, five such candidate drugs have entered phase II clinical trials in patients chronically infected with hepatitis C, including small molecule inhibitors of the HCV NS3 serine protease and NS5B RNA-dependent RNA polymerase. This review focuses on hepatitis C protease and polymerase inhibitors that have progressed to phase II clinical development, foreshadowing the era of STAT-Cs.
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PMID:Specific targeted antiviral therapy for hepatitis C. 1733 72

A one-step reverse transcriptase-polymerase chain reaction (RT-PCR) method was developed and optimized for the detection of duck hepatitis virus type 1 (DHV-1) using the Viral Gene-spin viral DNA/RNA extraction kit. A pair of DHV-1-specific primers was designed against the gene encoding RNA-dependent RNA polymerase (3D gene). Using RNA prepared from duckling liver samples infected with two reference and seven Korean field isolates of DHV-1, one-step RT-PCR with DHV1-specific primers amplified a 467-bp fragment. Under the same conditions, no amplification was observed for 14 other avian pathogenic viruses and bacteria. Using RNA prepared from serial dilutions of the DHV-1 with the supernatant of the uninfected duckling liver homogenate (10% w/v), the one-step RT-PCR assay was found to be sensitive to 10 50% egg lethal dose (ELD50) 0.1 ml(-1) of DHV-1. Furthermore, this method detected DHV-1 from the livers and allantoic fluid of duck embryos dying before 3 days postinoculation (PI) and of chicken embryos that were chilled at 3 days PI. Therefore, this one-step RT-PCR method is rapid, sensitive, and reliable, and can be readily adapted for detection of DHV-1 from other clinical samples.
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PMID:Development of one-step reverse transcriptase-polymerase chain reaction to detect duck hepatitis virus type 1. 1762 80

RNA polymerase (Pol) II catalyses DNA-dependent RNA synthesis during gene transcription. There is, however, evidence that Pol II also possesses RNA-dependent RNA polymerase (RdRP) activity. Pol II can use a homopolymeric RNA template, can extend RNA by several nucleotides in the absence of DNA, and has been implicated in the replication of the RNA genomes of hepatitis delta virus (HDV) and plant viroids. Here we show the intrinsic RdRP activity of Pol II with only pure polymerase, an RNA template-product scaffold and nucleoside triphosphates (NTPs). Crystallography reveals the template-product duplex in the site occupied by the DNA-RNA hybrid during transcription. RdRP activity resides at the active site used during transcription, but it is slower and less processive than DNA-dependent activity. RdRP activity is also obtained with part of the HDV antigenome. The complex of transcription factor IIS (TFIIS) with Pol II can cleave one HDV strand, create a reactive stem-loop in the hybrid site, and extend the new RNA 3' end. Short RNA stem-loops with a 5' extension suffice for activity, but their growth to a critical length apparently impairs processivity. The RdRP activity of Pol II provides a missing link in molecular evolution, because it suggests that Pol II evolved from an ancient replicase that duplicated RNA genomes.
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PMID:Molecular basis of RNA-dependent RNA polymerase II activity. 1800 86

Duck hepatitis can be caused by four types of viruses: duck hepatitis virus (DHV) type 1 (DHV-1), DHV-1a (a variant strain of DHV-1), DHV-2 and DHV-3. In Korea, duck hepatitis has been associated with two types of DHV-1, original DHV-1 type-specific strain (DHV-1s) and the recently reported DHV-1 variant strains (DHV-1v). The pathogenicity and pathological findings of ducklings infected with the recent DHV-1v isolates, AP-04114 and AP-04203, were almost identical to those infected with members of the DHV-1s, DHV-HS and the type-specific strain DRL-62. To be able to monitor the epidemiological patterns exhibited by the two Korean types, a specific gene-based differential diagnostic method based on multiplex polymerase chain reaction was developed. The primers selected were designed to bind to and amplify conserved regions within the RNA-dependent RNA polymerase (3D) gene, the complete capsid (P1) region or the 5'-untranslated region to distinguish between the DHV-1s and DHV-1v groups. The described multiplex polymerase chain reaction method was able to selectively recognize ducklings infected with either of the two groups of Korean isolates. The method was also able to distinguish between DHVs and other avian-originated RNA viruses. The detection limit of the diagnostic method was determined to correspond to 10(3) copies viral RNA and 100 pg used as starting template. As a result, the use of this test allows rapid and early diagnosis of two different virus types affecting the commercial duckling industry.
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PMID:Differential diagnosis between type-specific duck hepatitis virus type 1 (DHV-1) and recent Korean DHV-1-like isolates using a multiplex polymerase chain reaction. 1839 95

A synthetic cytomegalovirus (CMV) promoter-driven cDNA minigenome containing the enhanced green fluorescence protein (EGFP) gene as a reporter was derived from the genomic segment A of infectious bursal disease virus (IBDV). The 5'-end of the minigenome was fused to the transcription start site of the immediate early CMV promoter, and the hepatitis delta virus (HDV) ribozyme sequence was added at its 3'-end. We show that co-transfection of the minigenome with a plasmid encoding the IBDV RNA-dependent RNA polymerase VP1, results in a consistent increase of the EGFP expression, as measured by fluorescence microscopy and flow cytometry assays. Replication of the minigenome-derived transcript was evidenced by real-time RT-PCR analyses targeted to both the plus- and minus-sense strands. When cells were infected with IBDV and transfected with the plasmid carrying the minigenome, the minigenome was packaged and EGFP was found to be expressed in a second cycle of infection. These results show the potential use of this system as a new tool to characterize IBDV replication and genome packaging.
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PMID:Replication and packaging of an infectious bursal disease virus segment A-derived minigenome. 1856 33

Hepatitis C virus (HCV) is the major etiological agent of non-A, non-B hepatitis where no effective treatment is available. The HCV NS5B with RNA-dependent RNA polymerase (RdRp) activity is a key target for the treatment of HCV infection. Here we report novel NS5B polymerase inhibitors identified by virtual screening and in vitro evaluation of their inhibitory activities. On the basis of a newly identified binding pocket of NS5B, distinct from the nucleotide binding site but highly conserved among various HCV isolates, we performed virtual screening of compounds that fit this binding pocket from the available chemical database of 3.5 million compounds. The inhibitory activities of the in silico selected 119 compounds were estimated with in vitro RdRp assay. Three compounds with IC50 values of about 20 microM were identified, and their kinetic analyses suggest that these compounds are noncompetitive inhibitors with respect to the ribonucleotide substrate. Furthermore, the single-point mutations of the conserved residues in the binding pocket of NS5B resulted in the significant decrease of the RdRp activity, indicating that the binding pocket presented here might be important for the therapeutic intervention of HCV. These novel inhibitors would be useful for the development of effective anti-HCV agents.
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PMID:Identification of novel inhibitors of HCV RNA-dependent RNA polymerase by pharmacophore-based virtual screening and in vitro evaluation. 1933 75

RNA interference (RNAi) is a natural mechanism for suppressing or silencing expression of aberrant or foreign genes. It is a powerful antiviral strategy that has been widely employed to protect hosts from viral infection. Hepatitis E (HE) is an acute fulminant hepatitis in adults that has particularly high mortality in pregnant women. At this point in time, there is no vaccine or antiviral treatment that is effective against the infectious agent, HEV. The nonstructural polyprotein region possesses an RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of the viral RNA genome. RdRp is therefore regarded as one of the most attractive candidates for RNA interference (RNAi). In the present study, the high efficiency and specificity of siRNA were evaluated by Real-Time quantitative PCR and Western blot assays. Protective effects against HEV infection were achieved in A549 cells and in piglets. In piglets treated with a shRNA-RdRp-1 expression plasmid prior to HEV inoculation, HEV antigens were significantly reduced in the liver, spleen, and kidneys, and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were clearly decreased. These results suggested that RNAi is a potentially effective antiviral strategy against HEV replication and infection.
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PMID:Effective inhibition of hepatitis E virus replication in A549 cells and piglets by RNA interference (RNAi) targeting RNA-dependent RNA polymerase. 1957 49

Reoviruses are nonenveloped, segmented, double-stranded RNA viruses capable of infecting a wide range of invertebrate, vertebrate, fungus, and plant hosts. Though sporadic infection has been reported in a variety of reptilian species, infection of rough green snakes (Opheodrys aestivus) has not been previously described. Five wild-caught, adult rough green snakes were obtained by a zoological institution. Clinical deterioration was first noted in all snakes after 3 weeks in quarantine. Despite treatment, clinical decline progressed, and all 5 snakes died or were euthanized by 48 days post-arrival. Moderate, multifocal, acute, necrotizing hepatitis with hepatocellular syncytia was diagnosed in 1 snake. Two additional snakes had severe, diffuse, subacute to chronic pancreatitis. All 5 snakes had gastroenteric cryptosporidiosis. Electron microscopic examination of liver from the snake with hepatic lesions revealed scattered hepatocytes containing 1 or more intranuclear clusters of approximately 90 nm in diameter viral particles arranged in loose arrays. Polymerase chain reaction (PCR) amplification of a segment of the reovirus RNA-dependent RNA polymerase gene was performed on RNA extracted from tissues of all 5 snakes. PCR amplification of samples extracted from the snake with hepatic lesions resulted in a 109-base pair (bp) product. Phylogenetic analyses indicated the virus was a novel strain distinct from other reoviruses at a level consistent with species difference. The source of infection was unknown. PCR amplification of samples extracted from the other 4 snakes was negative.
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PMID:Orthoreovirus infection and concurrent cryptosporidiosis in rough green snakes (Opheodrys aestivus): pathology and identification of a novel orthoreovirus strain via polymerase chain reaction and sequencing. 2009 80

Viroids and viroid-like satellite RNAs from plants, and the human hepatitis delta virus (HDV) RNA share some properties that include small size, circularity and replication through a rolling-circle mechanism. Replication occurs in different cell compartments (nucleus, chloroplast and membrane-associated cytoplasmatic vesicles) and has three steps: RNA polymerization, cleavage and ligation. The first step generates oligomeric RNAs that result from the reiterative transcription of the circular templates of one or both polarities, and is catalyzed by either the RNA-dependent RNA polymerase of the helper virus on which viroid-like satellite RNAs are functionally dependent, or by host DNA-dependent RNA polymerases that, remarkably, viroids and HDV redirect to transcribe RNA templates. Cleavage is mediated by host enzymes in certain viroids and viroid-like satellite RNAs, while in others and in HDV is mediated by cis-acting ribozymes of three classes. Ligation appears to be catalyzed mainly by host enzymes. Replication most likely also involves many other non-catalytic proteins of host origin and, in HDV, the single virus-encoded protein.
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PMID:Rolling-circle replication of viroids, viroid-like satellite RNAs and hepatitis delta virus: variations on a theme. 2135 83

The first evidence of avian nephritis virus (ANV) in ducks is described. A diagnostic investigation was performed on three duck farms in Croatia. Samples from dead-in-shell ducklings and ducklings aged 30 days were collected and prepared for molecular and histopathological examination. Intestinal and liver samples were tested by polymerase chain reaction (PCR) for the presence of ANV, duck enteritis virus, duck hepatitis virus 1 and Derzsy's disease virus. Multiple tissues were collected for histological examination and lesions were found to be confined to the kidney and intestine. Moderate focal interstitial and periglomerular mononuclear cell infiltrates (mostly lymphocytes and plasma cells) were detected in the kidney. The duodenum showed rather diffuse pericryptal mononuclear cell hyperplasia (lymphocytes) and fibroplasia. ANV was detected by PCR in all the intestinal samples, while no other viruses were found. Sequence comparisons of the portion of the open reading frame 1b encoding the RNA-dependent RNA polymerase gene confirmed that the virus detected and sequenced from ducklings shared high nucleotide and amino acid identities with ANV-1. Additional work is required to determine the clinicopathological significance of ANV infection in ducks.
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PMID:Detection and characterization of avian nephritis virus in ducklings. 2150 37


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